Novel ketals of a-ring substituted estrones and related esters and ethers



United States Patent ()fifice Patented Mar. 16, 1955 3,173,915 NOVEL KETALS F A-RING SUBSTITUTED ES- TRONES ANT) RELATED FSTERS AND ETHERS Leland L. Smith, Malvern, Pa, assignor to American Home Products Corporation, New York, N31, a corporation of Delaware No Drawing. Filed Aug. 24, 1962, Ser. No. 219,125 2 Claims. (43!. 260-23955) A l R40- wherein R R and R represent a substituent selected from the group consisting of hydrogen, lower alkyl, and lower alkenyl; R represents a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower aralliyl, lower cycloalkyl and aeyl; and X represents a member selected from the group consisting of alkylenedioxymethylene, alkylenedit-hiomethylene, and alkylenethioxymethylene.

In the above definition the term lower alkyl as employed refers to those alkyl groups having from about 1 to 20 carbon atoms, and, more particularly, to those having less than about carbon atoms. The alkyl group may be normal or branched in structure although the normal chain is generally preferred. Some examples of these alkyl groups would be methyl, ethyl, propyl, butyl, isopropyl, pentyl, octyl, dodecyl and cetyl to name a few of such substituents. The term lower cycloalkyl refers to that substituent wherein the carbon atoms are joined in a carbocyclic ring which is generally a 5 or 6 membered ring but which may contain a smaller or larger number of carbon atoms subject to the practical limits of stability of such structures. Cyclohexyl would be an example of a preferred member of this class of substituents. The term lower aralkyl refers in general to an aromatic ring structure substituted by an alkyl group which may contain from about 1 to carbon atoms. An example of this type of substitution would be benzyl, phenylethyl, phenylisopropyl and the like. By the term acyl as employed herein is intended the mono-, di-, or poly-carboxy acid radical derived from a saturated or unsaturated organic acid by removal of the hydroxyl group. Such radicals as the alkanoyl radicals of corresponding acids such as acetyl, propionyl and butyryl derived from acetic, propionic, and butyiic acids and the like would therefore fall within the scope of this class of substituent. Radicals from aryl carboxylic acids, as benzoic acid, are also to be included. By the term lower alkenyl as it is employed herein, it is intended to refer to those unsaturated hydrocarbons containing at least one double bond in the chain such as allyl, vinyl and the like. In the present usage this term embraces all such radicals having less than 20 carbon atoms and preferably less than about 10 carbon atoms.

An essential portion of this novel structure is the substitution indicated by X in the 17-position of the steroid molecule. It is intended .by the definition of alkylenedioxymethylene as employed to define X that it embrace such ke-tals containing up to about 10 carbon atoms but preferably not more than about 4 carbon atoms. By the term alkylenethioxymethylene it is intended to include those keta-ls where one oxygen atom of the structure has been replaced by a sulfur atom. In a corresponding manner the termalkylenedithiomethylene as it is employed herein refers to those ketals wherein both oxygen atoms have been replaced by sulfur atoms.

The novel compounds of the invention may be prepared as illustrated by the following fiow diagram:

In the above reaction the known compounds l-alkyl or alkenyl estrone, 2-alkyl or alkenyl estrone or 4-alkyl or alkenyl estrone generally depicted by the structure (I), wherein the substituted group is shown extending into the A-ring at either of positions 1, 2, or 4, is ketalized at the 17-position by treatment with a suitable ketalizing agent such as ethylene glycol and p-toluenesulfonic acid in an inert solvent such as benzene or the like at temperatures up to the reflux temperature of the solvent employed for from 2 to 24 hours duration to form the corresponding 17-ketal (II) This structure may be etherified or acylated at the 3-position by any one of a number of conventional methods to obtain the corresponding 1-, 2-, or 4-alkyl or -alkenyl 3-substituted 17-lretalized estrones generally illustrated by (Ill).

In the above generalized preparation of the compounds of the invention where it is desired to prepare the 17- hemithioketal instead of the l7-alkylenedioxy substituted type, a reagent such as thioethanol may be substituted for the alkylene glycol employed in the ketalizing step.

The compounds of the invention are useful in the field of experimental pharmacology as well as being valuable as intermediates for further steroid synthesis in preparing new steroidal compounds. In addition, many of the compounds of the invention have been found to demon strate high antilipemic properties coupled with low feminizing action. Also, besides having capacity to regulate blood lipids, the compounds are useful for their general hormonal elteot, particularly in the female. Therefore many of the compounds would be expected to exhibit utility in those areas where estrogens are employed, such as female hypogonadism, amenorrhea, dysmenorrhea metrorrhagia, ovulation block and contraception, pregnancy maintenance, arteriosclerosis, osteoporosis, menopausal symptoms, infertility, regulation of water balance, functional uterine bleeding, and the like.

The novel compounds of the invention when contemplated for use in pharmaceutical products may be employed alone or in combination if desired with a large I injectables are to be prepared. Glycerine or the like may be added Where the compounds are to be administered as a syrup. Solid excipients, binders, extenders or carriers such as carboxymethylcellulose, starches, sugars and the like maybe employed where tablets or powders are to beused as a means of administration. The dosage of the compounds will vary with potency desired and the severity of the ailment, but in general can vary from about 0.5 to 100mg] kilo of body weight per day, depending upon the factors in the case involved.

In the preparation of the 17 -ketals of this invention as illustrated above, only one of a plurality of possible methods of ketalization has been disclosed. It should be understood that within the general framework of the invention other alternate means of ketal formation may be employed if desired. For instance, the process of 17- ketalization to form these novel compounds may be carried out by an exchange reaction which is known as exchange ketalization. In this method the 17-ketone to be ketalized is contacted with the ketal of another carbonyl compound such as the ethylene ketal of acetone, methylethylketone, mesityl oxide or the like in the presence of an acidic catalyst to effect a transfer of the ketal function from the latter compound to the former one. This reaction may be conducted either in the presence or absence of heating as specific conditions dictate. In any event one is thus able to obtain the 17-ketals of the invention.

It should further be noted that the present invention also comprehends the preparation of so-called open chain 17-ketals wherein the carbon atoms attached to the oxygenor sulfur atoms are not in fact joined together. However, the preparation of compounds such as these will become clear to those skilled in the art after consideration of the foregoing disclosure. In general the reaction is conducted at temperatures up to the reflux temperature of the solvent employed. It will vary somewhat therefore with the use of benzene, xylene and the like solvents in the reaction. The time of the ketalization, i.e., reflux,

Ancilysiacalcd. for C H O C, 76.95; H, 8.45.

Thin-layer chromatography using silica gel chromatoplates developed with hexane-ethyl acetate (4: 1) will show one component at R 0.12 [l-methylestrone at R 0.07]; using hexane-ethyl acetate (1:1), R 0.70 [l-methylestrone at 11 50.59]. 7 I

EXAMPLE 2 I 7,] 7-ethy lenedioxy-2 -met hy lestra-l ,3 ,5 (1)4."ien-3-0l Reflux a mixture of 1.0g. of Z-methylestrone [lriarte and Ringold, Tetrahedron, 3, 28 (1958)], 150 rug/of ptoluenesulfonic acid, 100 ml. of benzene and 10 ml.fo f ethylene glycol for 24 hours with continuous removal of water. Cool the mixture, and wash with aqueous sodium bicarbonate solution. Wash the benzene layer with Water, dry over anhydrous magnesium sulfate, and evaporate under vacuum. Dissolve the solids thus obtained in ethyl acetate and concentrate slightly, adding petroleum ether to cause cloudiness. Leave standing for several hours, then filter and dry the precipitated product to obtain the product of this example.

' estrone [Pattom JfOrg. Chem., 27, 910 (1962); Holton,

Will vary from about 2 to 24hours duration on an aver- ,7

age. a

The invention will be further illustrated by the several examples of preparation of selected members of the series which follow. It is, of course, to be understood that these examples are set forth purely by way of illustration and are not intended to limit the scope of the invention in any manner. For a legal definition of the proper scope of the invention, attention may only be directed to the several appended claims.

EXAMPLE 1 1 7,1 7-ethylenedi0xy-1-methylestra-1,3,5 (10)-trien-3-ol Reflux overnight a mixture of 970 mg. of l-methylestrone [C. Djerassi et al., I. Am. Chem. Soc., 72, 4540 (1950)], 150 mg. of p-toluenesulfonic acid, 100 ml..of

benzene, and 10 ml. of ethylene glycol with removal of 2.99 6.41 6.5514,. etc.

max.

I ethyleneglycol with continuous removal of water.

and wash with aqueous sodium bicarbonate solution.

example.

J. Org. Chem., 27, 357 (1962)], and 75 mguof p-toluenesulfonic acid in 75 ml. of benzene containing 5 ml. of Cool Wash the benzene layer with water, dry over anhydrous magnesium sulfate, and concentrate to a small volume. After chilling, the product precipitates, and can be recovered by filtration. For purification dissolve the solids in hot acetone, concentrate somewhat, and add hexane to cause precipitation of product. 'After several hours filter and dry the crystalline product to obtain the product of this example.

" EXAMPLE 4 71,1 7-ethylenedioxyf-propylaste -1,3,5 (10)-trieri-3-0l vacuum. crystallize the solid residue from methanol and from acetone-hexane mixtures to obtain the product of this example.

EXAMPLE 5 1 2-allyl-1 7,1 7-e thylenedioxyestra-1 ,3,5 (10 -trien-3-0l In the same manner as described in Example 1, 1.0 g. of 2-allylestrone [Patton, J. Org. -Chem., 27, 910 (1962); Holton, J. Org. Chem., 27, 357 (1962)] may be converted to the 17-ethylene ketal which is the product of this EXAMPLE 6 4-allyl-1 7 ,1 7 ethyl enedi oxy estra-I ,3,5 (1 0 -trien-3-0l In the same manner as described in Example 1, 4 allylestrone [Patton, J. Org. Chem., 27, 910 (1962); Holton, J. Org. Chem., 27, 357 (1962)] may be converted to the 17-ethylene ketal which is the product of this example.

EXAMPLE 7 One gram of Z-[d-methylallyhestrone [Patton, J. Org.

Chem, 27, .910 (1962)] may be treated with ethylene glycol in the same way as described in Example 1 in order to obtain the above-named product.

EXAMPLE 8 3-acetoxy-1 7 ,1 7-efl2ylenedi0xy-1-methylestra-1,3,5 (10 triene Dissolve 100 mg. of l-methylestrone 17-ethylene ketal in 10 ml. of dry pyridine, and add 3 ml. of acetic anhydride. Leave standing at room temperature for 24 hours, then remove solvents under vacuum. Dissolve the residue thus obtained in acetone, concentrate under vacuum slightly, and add hexane. Leave standing for several hours, then filter the crystalline product or: this example.

EXAMPLE 9 3-benz0yl0xy-17,17-ethyZenedioxy-I -methylestra- 1,3,5 (1 -triene Dissolve 300 mg. of l-methylestrone 17-ethylene ketal in 25 ml. of 3% potassium hydroxide solution, and cool to 0. Add 3 ml. of benzoyl chloride with good stirring; as the benzoate forms it will be precipitated from solution. Leave standing for 30 minutes, then filter and dry the pure benzoate to obtain the product of this example.

EXAMPLE l0 17,17-elhylenedioxy-B-methoxy-1 -rr1ethylestm-],3,5(10)- triene Treat a solution of 1.5 g. of l-methylestrone l7-ethylene ketal in 250 ml. of boiling methanol and 500 ml. of 10% aqueous sodium hydroxide solution dropwise with 80 ml. or" dimethylsulfate. Adjust the addition rate to last for 20 minutes. Then boil the mixture for 30 minutes, and add 170 ml. of 40% sodium hydroxide solution, followed by dropwise addition of an additional 80 ml. of dimethylsulfate added over 20 minutes. Boil the mixture for one hour, cool, and dilute with 300 ml. of water. After cooling further, filter and dry the precipitated product to obtain the product of this example.

EXAMPLE 11 3 -erh0xy-1 7 ,1 7-ezhylenedioxy-I -methyZestra-1,3,5 (l 0 iriene Treat a solution of 1.0 g. of l-methylestrone 17-ethylene ketal in 50 ml. of ethanol with ml. of ethyl bromide and 350 mg. of sodium hydroxide. Reflux the mixture for 20 hours, then evaporate the solvents under vacuum. Dissolve the residue in carbon tetrachloride, and Wash the carbon tetrachloride solution with 5% sodium hydroxide solution and then with water. Evaporate the Washed carbon tetrachloride solution and crystallize the residue obtained from methanol to obtain the product of this example.

EXAMPLE 12 3 -allyloxy-l 7 ,1 7 -ethy lenedioxy-I -methylestra-1 ,3,5 (1 0) triene Reflux a mixture of 500 mg. of l-methylestrone 17- ethylene ketal, 15 ml. of ethanol, 2 ml. of allyl bromide, and 140 mg. of sodium hydroxide for 1 8 hours. Remove the solvents under vacuum, and take up the residue in carbon tetrachloride. Wash the carbon tetrachloride solution with 5% sodium hydroxide solution and with water, and then dry and evaporate under vacuum. Recrystallize the solids thus obtained from methanol to obtain the product of this example.

EXAMPLE 13 3-cycl0pentyloxy-1 7,1 7-ethylenedi0xy-1-methylestra- 1,3,5 1riene Reflux a mixture of 1.0 g. of l-methylestrone 17-ethylene ketal, 30 ml. of ethanol, 10 m1. of cyclopentyl bromide, and 750 mg. of sodium hydroxide for 24 hours. Remove the solvent under vacuum, and dissolve the residue in carbon tetrachloride. Wash the carbon tetrachloride solution with 5% sodium hydroxide solution and with Water, and finally evaporate under vacuum. Recrystallize the solid residue thus obtained from methanol to obtain the purified 3-cyclopentyloxy-17,17-ethylenedioxy-l-rnethylestra-l,3,5 (10)-triene of this example.

EXAMPLE 14 3-benzyl0xy-1 7,1 7-cthylenedioxy-J-methylestra-1,3,5 (10 triene Reflux for 18 hours 1.0 g. of l-methylestrone 17-ethylene ketal, 50 ml. of ethanol, 5 ml. of benzyl bromide, and 350 mg. of sodium hydroxide. Then remove the solvent under vacuum and dissolve the solids llll carbon tetrachloride. Wash the carbon tetrachloride solution with 5% sodium hydroxide solution and with water. Then evaporate the solution and recrystallize the solids thus obtained from acetone to obtain the product of this example.

EXAMPLE 15 1-methyl-17,1 7-trimethy lenedioxy astral-1,3,5 (l 0) trien- 3-01 EXAMPLE 16 1 7,1 7-ethylenethi0xy-1-methyles2ra-1 ,3,5 (10) -trien-3-0l Reflux a solution containing 500 mg. of l-methylestrone and 30 mg. of ptoluenesulfonic acid in 75 ml. of benzene containing 2 ml. of Z-mercaptoethanol for 6 hours, With continuous removal of Water via a Dean-Stark apparatus. Cool the mixture, and Wash with saturated sodium bicarbonate solution and then with Water. Evaporate the dried benzene solution under vacuum. Crystallize the solids thus obtained from methanol to obtain the pure 17,17- ethylenethioxy-l-methylestra-1,3,5 (10)-trien-3-ol which is the product of this example.

EXAMPLE 17 1 7 ,1 7-ethyleneaiihio-Z-methylestra-1,3,5 (l 0 -lrien-30l Cool a mixture of 1.0 g. of Z-methylestrone, 5 ml. of ethanedithiol and 25 ml. of chloroform to 5 and bubble anhydrous hydrogen chloride through the solution for three hours. Then remove the solvent under vacuum, and take up the residue in Warm acetone, concentrate slightly, and cool. The pure product of this example will be deposited.

I claim:

11. 17,17-ethylenedioxy-l-methylestra-1,3,5(10) trien- 3-0 2. l-methyl-17,l7 trimethylenedioxyestra 1,3,5(10)- trien-3-ol.

References Cited by the Examiner UNITED STATES PATENTS 4/62 Bernstein et a1 260-3974 OTHER REFERENCES Djerassi et al.: J.A.C.S. 72, page 4540 (1950). Holton: J. Org. Chem. 27, page 910 (1962). Iriarte et al.: Tetrahedran 3, page 28 (1958). Lowenthal: Tetrahedran 6, page 269-303 (1959).

LEWIS GOTTS, Primary Examiner. 

1. 17,17-ETHYLENEDIOXY-1-METHYLESTRA-1,385(10) - TRIEN3-OL. 